Tear film disturbances account for eye symptoms in millions of Americans. At the present time, treatment primarily consists of replacing a defective tear film with artificial tear substitutes which are sold over-the-counter. The major limitation of these products is their short retention time in the eye. Patients must apply drops as often as every hour to obtain comfort from these products. Recent accomplishments have focused on developing aqueous solutions containing components which will stabilize the tear film or replace specific deficiencies.
A normal tear film is the product of: (1) aqueous secretion by the lacrimal gland and accessory lacrimal glands; (2) secretion of mucous primarily by the goblet cells of the conjunctiva; and, (3) lipids secreted by the meibomian gland and the glands of Zeis and Moll in the lids. Mucin, the innermost layer (0.035 .mu.m), wets the lipophilic epithelial surface of the cornea with the middle aqueous layer. The aqueous layer (7 .mu.m) contains dissolved proteins, carbohydrates, glycoproteins, oxygen, and inorganic salts. The outer lipid layer (0.1 .mu.m) retards evaporation of the aqueous component.
Dry eye syndrome or keratoconjuctivitis sicca (KCS) can occur secondarily to many autoimmune diseases, and as a result of abnormalities in the precorneal tear film physiology. Besides an awareness of a chronically irritable sore eye by the patient, clinicians can diagnose dry eye syndrome by various measurements. These include a tear breakup time of 10 seconds or less in the absence of blinking, or a Schirmer test value of 5 mm or less. The latter involves leaving a standard strip of filter paper under the lower lid for 5 minutes. Other measurements are also helpful and include an observation of a smaller than normal marginal tear strip upon slitlamp examination, and/or a positive rose bengal stain which detects the presence of precipitated mucin and devitalized cells.
The stimulation of aqueous tears by a drug acting on the autonomic nervous system is an approach that had in the past limited success via a systemic route and little success via a topical route of administration. For example, some ophthalmologists have recommended oral ingestion of very dilute solutions of the cholinergic, pilocarpine, to stimulate tear secretion. However, unpleasant side effects have discouraged widespread use of ingested pilocarpine.
The stimulation of aqueous tears by the systemic or oral route has the undesirable side effect of causing systemic drug reactions by materials such as pilocarpine and other cholinergics. Moreover, by the time the active drug transfers itself through the body to the eye, its effect is significantly diluted. To date, there is no known effective composition for topical route of administration to treat dry eye syndrome.
As earlier indicated, the treatment with tear replacement compositions is not totally satisfactory because of their short retention time in the eye. Often the use by sufferers of dry eye syndrome of tear replacement products must continually apply drops even as often as every hour to obtain eye comfort. Moreover, especially for wearers of contact lenses, this problem of short time retention becomes quite real, rendering tear replacement unsatisfactory. In short, sufferers of dry eye syndrome are currently, for all practical purposes, excluded from the possibility of wearing contact lenses, since those lenses and their effective use, to say nothing of their comfortable use, necessarily depends upon adequate tear production.
It can be seen therefore that there is a very real and continuing need for an effective tear stimulant composition which can be administered topically. This invention has as its primary objective the fulfillment of this need.
Another objective of the present invention is to synthesize a series of compounds which have the utility of functioning effectively as tear, or in other words lacrimal, stimulants.
A still further objective of the present invention is to provide ophthalmic compositions which can function effectively as tear stimulants when topically administered to the eye.
A yet further objective of the present invention is to provide topical compositions which are not only effective tear stimulants but which also are non-toxic to the eye, and safe and effective, and as well cause little or no side effects.
An even further objective of the present invention is to provide topical ophthalmic compositions which stimulate tear production within the eye, thus eliminating the need for continual application of drops on a regular and frequent basis, such as is now required with currently sold tear replacement products.
Still another objective of the present invention is to provide a method of treatment of dry eye syndrome to stimulate the eye itself to produce more tears in a safe and efficacious manner.
Yet another objective of the present invention is to provide a method of inducing tear stimulation by topical administration of an ophthalmically active tear stimulant. The method of accomplishing these as well as other objectives of the invention will become apparent from the detailed description which follows hereinafter.